The overall goal of this research is to elucidate the mechanisms by which the mitochondrial antioxidant enzyme, manganese containing superoxide dismutase (MnSOD), modulates the carcinogenesis action of tumor promoters and UV radiation. Our studies in the previous funding period indicate that overexpression of MnSOD suppresses the incidence and multiplicity of papillomas in the 7-12-dimethylbenz (a) anthracene (DMBA)/ 12-O tetradecanoylphorbol-13-acetate (TPA) multistage skin carcinogenesis model. MnSOD- mediated tumor suppression is, in part, mediated by reduction of AP-1 activation and expression of proliferation related genes. Unexpectedly, reduction of MnSOD by heterozygous knockout of the MnSOD gene does not result in increased tumor incidence or multiplicity using the DMBA/TPA model. The lack of increased susceptibility to DMBA/TPA-induced tumors in the MnSOD knockout mice is due, in part, to an increase in both apoptosis and proliferation after TPA treatment. Administration of MnSOD mimetic without interfering with TPA-induced apoptosis is very effective in reducing DMBA/TPA-induced skin papillomas in MnSOD-deficient mice. We also found that the increased apoptosis in MnSOD-deficient mice is associated with increased p53 accumulation in the mitochondria and reduced MnSOD expression. Based upon these novel findings, we propose that activation of p53 enhances apoptosis, in part, via modulation of mitochondrial antioxidant defense capacity and that the tumor suppression effect of MnSOD is mediated, in part, by p53. Two specific aims are designed to test these hypotheses using TPA and UV radiation as the prototype oxidative stress generating carcinogens. The results of the proposed studies will provide insights into the common mechanisms by which MnSOD levels modulate apoptosis induced by chemical or UV radiation during an early stage of skin carcinogenesis. They will also enhance our understanding of the p53-dependent and -independent tumor suppression role of MnSOD. Identification of a common mechanism by which tumor promoter and UV radiation cause apoptosis would provide a means for developing a mechanistic based intervention that would prevent the development of skin cancers caused by a wide range of carcinogens. Thus, this timely and important study will likely have a large scale impact on human health. PUBLIC HEALTH RELEVANCE: Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have recently found that by modulating the interaction between an essential antioxidant enzyme, MnSOD, and a key tumor suppressor protein, p53, the incidence of skin tumors can be drastically reduced. In this application we will extend from this novel finding to determine how this interaction acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and other oxidative stress generating chemical carcinogens.